Screening GGC repeat expansion in the <em>NOTCH2NLC</em> in early-onset dementia: The Longitudinal Study of Early Onset Dementia and Family Members (LEAF) Study

Alzheimers Dement (Amst). 2026 Sep 27;18(3):e70482. doi: 10.1002/dad2.70482. eCollection 2026 Jul-Sep.

ABSTRACT

BACKGROUND: Neuronal intranuclear inclusion disease (NIID) is neurodegenerative disorder caused by GGC repeat expansion in NOTCH2NLC. Given its frequency in young East Asian adults and overlap with cognitive impairment in young adults, a key feature of early-onset dementia (EOD), we screened NOTCH2NLC GGC repeat expansions in Korean patients with EOD.

METHODS: We screened NOTCH2NLC GGC repeat expansions in 410 Korean patients with EOD using repeat-primed and amplicon length polymerase chain reaction. Plasma biomarkers in adult-onset leukodystrophy were additionally measured using Simoa-based ultrasensitive immunoassays.

RESULTS: GGC repeat expansions were not identified in early-onset Alzheimer's disease (AD) or frontotemporal dementia (FTD), while four of eleven patients with adult-onset leukodystrophy (36.3%) had abnormal expansions. Plasma neurofilament light chain (NfL) level was lower in NIID than in colony-stimulating factor 1 receptor-related disorder.

DISCUSSION: These findings support recent arguments that the concept of NOTCH2NLC-related GGC repeat expansion disorder (NRED) should be reconsidered. Plasma NfL may be useful in differential diagnosis of adult-onset leukodystrophy.

PMID:42802826 | PMC:PMC13616204 | DOI:10.1002/dad2.70482